International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #67: Regulation of Glucose Metabolism in Liver Part 3 of 11

Glycogen metabolism is regulated by reciprocal changes in the activities of glycogen synthase and glycogen phosphorylase (Figure 13.2). Net glucose production from glycogen occurs when phosphorylase activity is higher than synthase activity. Activation of glycogen phosphorylase is the culmination of a “glycogenolytic cascade” that is initiated by the binding of glucagon or β-adrenergic agonists to their receptors in liver cells [5]. The release of these hormones is stimulated by stressors such as fasting and exercise that require increased glycogenolysis to maintain glycemia. Upon activation of their hepatocyte G-protein coupled receptors, and coordinated activation of adenylate cyclase by the Ges heterotrimeric GTP-binding protein, glucagon causes a rapid rise in intracellular cAMP concentrations. This molecule causes the activation of cAMP-dependent protein kinase (PKA), which in turn leads to phosphorylation and activation of phosphorylase kinase. Finally, phosphorylase kinase phosphorylates glycogen phosphorylase, thereby converting the enzyme from its inactive (phosphorylase b) to its active (phosphorylase a) form (Figure 13.2) [12].

Similar to glycogen phosphorylase, glycogen synthase is phosphorylated under fasting conditions. However, unlike phosphorylase, phosphorylation of glycogen synthase occurs at multiple serine sites and inactivates rather than activates the enzyme [12]. Phosphorylation of glycogen synthase is catalyzed primarily by PKA and glycogen synthase kinase 3 (GSK3). In sum, a net activation of glycogenolysis is promoted during fasted or insulinopenic conditions via phosphorylation of glycogen phosphorylase and glycogen synthase, leading to activation of the former and decreased activity of the latter (Figure 13.2).

While glycogenolysis is promoted by phosphorylation of glycogen synthase and glycogen phosphorylase, a critical regulatory event for stimulating glycogen synthesis during feeding is to dephosphorylate these enzymes. The reciprocal regulation of glycogen synthase with phosphorylase and its overall participation in regulating glycogenolysis requires some consideration in our discussion of hepatic glucose production, although a more complete discussion of its role in glycogen synthesis and glucose disposal will be discussed later. A common protein phosphatase, protein phosphatase 1 (PP-1), is used to dephosphorylate both glycogen synthase and glycogen phosphorylase. The dephosphorylation mechanism is complemented by several other regulatory events. G6P binds to glycogen synthase, causing a conformational change that renders it a better substrate for PP-1. Similarly, glucose binds to glycogen phosphorylase a, again causing a conformational change that enhances its rate of PP-1-mediated dephosphorylation and decreases enzyme activity [12]. The expression of the glucose transporter GLUT2 and the glucose phosphorylating enzyme glucokinase in liver allows the levels of free glucose and G6P to rise in proportion to changes in circulating glucose concentrations, contributing to effective regulation of glycogen phosphorylase and glycogen synthase activities. In addition, the rise in insulin levels in the postprandial state activates a branch of the insulin signaling pathway that includes PI-3 kinase and Akt (protein kinase B) and stimulates phosphorylation and inhibition of glycogen synthase kinase 3 (GSK-3) [12], and other poorly understood mechanisms [13]. This results in less GSK-3-mediated phosphorylation of glycogen synthase, leaving the enzyme in a less phosphorylated, and therefore more active condition. The ability of glycogenolytic flux to be altered rapidly is an essential first response to ingestion of carbohydrate or upregulation of gluconeogenesis.

The common use of PP-1 for dephosphorylation of both glycogen synthase and glycogen phosphorylase is not a coincident, and is an example of spatial organization in the regulation of hepatic carbohydrate metabolism. It is now appreciated that enzymes of glycogen metabolism, including the regulatory enzyme PP-1, are assembled in a multiprotein complex that is also associated with the glycogen particle. This spatial association also contributes to appropriate activation or suppression of glycogen synthesis in response to changes in nutritional conditions. The scaffolding proteins that organize glycogen metabolism are known collectively as glycogen-targeting subunits of PP-1 [12].

In principle, glycogen synthesis and glycogenolysis are reciprocally regulated by the antithetic control of glycogen synthase and glycogen phosphorylase (as discussed earlier). It should be noted, however, that this reciprocal regulation may not always be complete. Thus, in controlled experimental circumstances, such as during hyperinsulinemic-euglycemic clamp protocols in humans, a decrease in net hepatic glycogenolysis can be demonstrated, which is due to a large activation of glycogen synthase flux, but without a decrease in phosphorylase flux [14]. Thus, glycogenolysis can continue during periods of net glycogen synthesis, suggesting that a significant portion of the phosphorylated glucose derived from glycogenolysis in liver can be recycled back into glycogen (i.e., glycogen cycling). Thus, control of liver glycogen metabolism should not be viewed simply as regulation of perfectly reciprocal “on” and “off ” switches, but more as control of net flux via a predominance of activity of one pathway relative to the other.